RESUMEN
We describe two male siblings with diabetes mellitus caused by mitochondrial 3243 mutation. The level of heteroplasmy in peripheral blood leucocytes was determined by a last-cycle hot PCR method. The younger brother, who had 39% heteroplasmy, developed diabetes at age of 25, and demonstrated a lean body habitus and blunted insulin secretion. The elder brother, who had 22% heteroplasmy, was diagnosed at the age of 42. The younger brother showed a higher increment of serum lactate after exercise. In these siblings the level of heteroplasmy in their peripheral blood leucocytes appeared to be associated with age of onset of diabetes.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus/genética , Mutación Puntual , ARN de Transferencia de Leucina/genética , Adulto , Edad de Inicio , ADN Mitocondrial/sangre , Diabetes Mellitus/sangre , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Kinya Kuriyama. The presentations were (1) Modulation of neuroreceptors and ion channels by alcohol, by T. Narahashi; (2) Inhibition by ethanol of NMDA and AMPA receptor-channels, by P. Illes, K. Wirkner, W. Fischer, K. Mühlberg, P. Scheibler, and C. Allgaier; (3) Effects of ethanol on metabotropic glutamate receptors, by K. Minami; (4) Acute alcohol actions on the 5-HT3 ligand-gated ion channel, by D. Lovinger; (5) Inhibition of NMDA receptors by MK801 attenuates ethanol-induced taurine release from the hippocampus, by F. Lallemand, R.J. Ward, and P. DeWitte; and (6) Effect of ethanol on voltage-operated Ca2+ channels in hepatic stellate cells, by T. Itatsu, Y. Takei, H. Oide, M. Hirose, X. E. Wang, S. Watanabe, M. Tateyama, R. Ochi, and N. Sato.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Receptores AMPA/efectos de los fármacos , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Canales de Calcio/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Canales Iónicos/efectos de los fármacos , Canales Iónicos/fisiología , Receptores AMPA/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Receptores de Serotonina 5-HT3 , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
BACKGROUND: Hepatic stellate cells have been reported to play important roles in the regulation of hepatic microcirculation via cell contraction. Increase in intracellular calcium concentration is required to induce cell contraction. We have already reported the existence of L-type voltage-operated Ca2+ channels (VOCC), such as smooth muscle cells. On the other hand, alcohol has been known to disturb hepatic microcirculation. In this study, we evaluated the effect of acute and chronic treatment of alcohol on VOCC in rat hepatic stellate cells. METHODS: Stellate cells isolated from rats were cultured with or without 100 mM ethanol for up to 14 days. VOCC were detected by the patch clamp technique. Cells cultured for 14 days without ethanol were exposed to ethanol to investigate calcium current during membrane depolarization. alpha-Smooth muscle actin (alpha-SMA) was stained by indirect immunofluorescence. RESULTS: In the control model, VOCC were recognized in cells cultured for more than 7 days. Detection of VOCC increased from 9% on day 7 to 55% on day 14. On the other hand, VOCC in cells treated chronically with 100 mM ethanol appeared earlier than in the control and the incidences were significantly higher than those of the control accompanied with an early activation of cells. In contrast, simultaneous exposure to ethanol during the membrane depolarization inhibited Ca2+ current. CONCLUSIONS: The expression of Ca2+ channels in stellate cells were up-regulated by the chronic treatment of alcohol accompanied with the transformation to myofibroblast-like phenotype. However, alcohol itself inhibited Ca2+ current.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Hígado/efectos de los fármacos , Actinas/efectos de los fármacos , Actinas/metabolismo , Animales , Canales de Calcio/fisiología , Células Cultivadas , Endotelio/citología , Femenino , Hígado/citología , Hígado/fisiología , Ratas , Ratas WistarAsunto(s)
Infecciones por HTLV-I/complicaciones , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Hepatitis B/complicaciones , Linfoma de Células T/complicaciones , Neoplasias Gástricas/complicaciones , Adulto , Gastroscopía , Humanos , Linfoma de Células T/diagnóstico por imagen , Linfoma de Células T/patología , Linfoma de Células T/cirugía , Masculino , Radiografía , Cintigrafía , Estómago/microbiología , Estómago/patología , Estómago/virología , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
We previously reported stellate (Ito) cells possess voltage-activated Ca2+ current. The activation of stellate cells has been indicated to contribute to liver fibrosis and the regulation of hepatic hemodynamics. The aim of this study was to investigate the relationship between voltage-activated Ca2+ current and activation of stellate cells. Voltage-activated Ca2+ current in stellate cells isolated from rats were studied using whole-cell patch clamp technique. L-type voltage-activated Ca2+ current was hardly detected in stellate cells cultured for less than 9 days. Ca2+ current was detected 12.5 and 69% of cells at the 10th and 14th day of culture, respectively. BrdU incorporation indicated cell proliferation was recognized over 50% of cells at the 3rd and 5th day of culture, respectively, then decreased significantly in a time-dependent manner. On the other hand, the expression of alpha-smooth muscle actin indicated cell activation increased from 7th day of culture and collagen type I mRNA appeared remarkably in cells cultured for more than 10 days. In this study, we concluded L-type voltage-activated Ca2+ current was recognized in activated stellate (myofibroblast-like) cells.
Asunto(s)
Canales de Calcio/metabolismo , Hígado/metabolismo , Músculo Liso/metabolismo , Actinas/análisis , Animales , Western Blotting , División Celular , Células Cultivadas , Colágeno/genética , Desmina/análisis , Femenino , Técnicas de Placa-Clamp , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Hepatic stellate cells (HSCs) have L-type voltage-operated Ca2+ channels (VOCC). However, the effect of ethanol on VOCC is unknown. To investigate the mechanism of ethanol-induced liver injury, the effect of ethanol on VOCC in HSCs was studied. In control cells, VOCC revealed by patch clamp techniques were not detected in cells cultured for less than 7 days; however, a faint VOCC mRNA by reverse-transcription polymerase chain reaction was recognized at the 5(th) day of culture. Detection of VOCC increased from 8% on day 7 to over 50% on day 14 in controls. With ethanol (100mM), it increased from 12% on day 5 to 100 % on day 14. Furthermore, expression of alpha-smooth muscle actin, shown as transformation to a myofibroblast, was recognized in ethanol-treated cells earlier and stronger than that in controls. VOCC were up-regulated by the treatment with ethanol associated with the induction of transformation to myofibroblasts.
Asunto(s)
Canales de Calcio/genética , Etanol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Transcripción Genética , Actinas/genética , Animales , Calcio/metabolismo , Canales de Calcio/fisiología , Canales de Calcio Tipo L , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Fibroblastos/citología , Cinética , Hígado/citología , Hígado/efectos de los fármacos , Técnicas de Placa-Clamp , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transcripción Genética/efectos de los fármacosRESUMEN
Prostaglandin E1 (PGE1) has been reported to have, experimentally and clinically, a protective effect against liver damage. This effect may result from the relaxation of hepatic stellate cells, whose contraction induces vasoconstriction of hepatic sinusoids. However, prostaglandins are unstable and a new drug delivery system is necessary to administer a sufficient amount of prostaglandin to achieve a protective effect in the liver. The aim of the study is to investigate the effects of lipo-prostaglandin E1 (lipo-PGE1) which has a novel drug delivery system on the stellate cell contraction induced by endothelin-1 in vitro. Lipo-PGE1 inhibited endothelin-1-induced stellate cell contraction in concentrations of 10, 30 and 50 ng/mL. Therefore, lipo-PGE1 may show a cytoprotective effect in the liver through the relaxation of stellate cells and an increase in the hepatic sinusoidal blood flow.
Asunto(s)
Alprostadil/farmacología , Hígado/citología , Alprostadil/metabolismo , Animales , Células Cultivadas , Endotelina-1/farmacología , Masculino , Ratas , Ratas WistarRESUMEN
MS-818 is a novel synthetic pyrimidine compound that stimulates nerve regeneration and promotes synthesis of various growth factors and differentiation of astrocytes. Effects of MS-818 on gastric epithelial cells were assessed using a wound repair model with primary cultured gastric epithelial cells from rabbits. A round wound with a constant cell-free area was created and the process of restoration was monitored by measuring wound size every 12 h. Cell proliferation was monitored by sequential staining with BrdU. As previously reported, EGF (10 ng/ml) accelerated wound repair by promoting cell migration and proliferation. Although MS-818 alone had no effects, MS-818 (10-100 microM) enhanced EGF-induced acceleration of gastric epithelial restoration, including cell migration and proliferation. Although the detailed mechanism of action of this agent is still unclear, MS-818 might have favorable effects on in vivo gastric mucosal repair.
Asunto(s)
Factor de Crecimiento Epidérmico/farmacología , Mucosa Gástrica/efectos de los fármacos , Pirimidinas/farmacología , Úlcera Gástrica/fisiopatología , Cicatrización de Heridas/efectos de los fármacos , Animales , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Sinergismo Farmacológico , Mucosa Gástrica/citología , Mucosa Gástrica/fisiología , Masculino , Fármacos Neuroprotectores/farmacología , Conejos , Úlcera Gástrica/patologíaRESUMEN
A case of early esophageal adenocarcinoma arising in Barrett's esophagus is reported. Many cases of Barrett's esophagus, which is considered a premalignant condition, have been reported in Western countries, but few cases have been reported in Japan. The patient, a 53-year-old man with nausea and vomiting, was a drinker (four glasses wine/day for about 30 years), but did not smoke. He had had a hiatal hernia of the esophagus. Since endoscopic biopsies demonstrated an early adenocarcinoma in Barrett's esophagus, subtotal esophagectomy was performed. In the resected esophageal material, Barrett's esophagus was seen to extend for 12 cm. In addition to the cancer detected preoperatively as a 0-IIc lesion (1.5 cm in diameter), a 0-IIb lesion (1.5 cm in diameter) was also detected in the postoperative survey. Both lesions were well differentiated adenocarcinoma that had invaded only into the lamina propria mucosa. The 23 cases of early adenocarcinoma in Barrett's esophagus that have been reported in Japan were reviewed, and it was learned that the present case is the second of multiple early cancer arising in Barrett's esophagus so far reported in Japan.
Asunto(s)
Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Neoplasias Primarias Múltiples/patología , Lesiones Precancerosas/patología , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
HLA antigen phenotypes and BglII restriction fragment length polymorphism of T cell receptor beta-chain (TCR beta) gene were analyzed in 61 patients with Graves' disease and 50 patients with Hashimoto's thyroiditis. The antigen frequency of HLA-Bw46 in both Graves' disease (23.0%) and Hashimoto's thyroiditis (24.0%) was significantly higher than that in normal population (8.0%), with relative risks (RR) of 3.45 [corrected P (Pc) less than 0.009] and 3.66 (Pc less than 0.02), respectively. Significantly increased frequency of HLA-B51 antigen was also found in Hashimoto's thyroiditis (40.0% vs. 16.3% in controls; RR, 3.42; Pc less than 0.002). Hybridization of BglII-digested DNA with TCR beta probe revealed two alleles of 9.3 and 8.6 kilobases. The allele frequency of 8.6 kilobases in Graves' disease (79%) and Hashimoto's thyroiditis (76%) was significantly higher (P less than 0.01 and P less than 0.05, respectively) than that in controls (64%). The frequency of homozygous state 8.6/8.6 was significantly increased in both Graves' disease (62%) and Hashimoto's thyroiditis (60%) over that in controls (39%); the RR of 8.6/8.6 in Graves' disease and Hashimoto's thyroiditis were 2.55 (P less than 0.01) and 2.31 (P less than 0.05), respectively. These results indicate that in Japanese subjects at least two loci are involved in the susceptibility to Graves' disease and Hashimoto's thyroiditis, one related to HLA and another to TCR beta.
Asunto(s)
Genes , Enfermedad de Graves/inmunología , Antígenos HLA/análisis , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Antígenos de Linfocitos T/genética , Tiroiditis Autoinmune/inmunología , Alelos , Sondas de ADN , Femenino , Genotipo , Enfermedad de Graves/genética , Humanos , Japón , Masculino , Hibridación de Ácido Nucleico , Fenotipo , Receptores de Antígenos de Linfocitos T/análisis , Tiroiditis Autoinmune/genéticaRESUMEN
We studied neurohypophyseal function in 12 women with postpartum hypopituitarism (Sheehan's syndrome) by measuring plasma arginine vasopressin concentrations during 5% hypertonic saline infusions. All patients had a history of obstetric shock or massive bleeding, and were receiving cortisol and/or L-T4 replacement therapy. None had any symptoms of diabetes insipidus. The mean basal plasma vasopressin level in the patients [0.6 +/- 0.1 (+/- SE) pmol/L] was significantly lower (P less than 0.01) than that in normal adults (2.5 +/- 0.5 pmol/L; n = 12), whereas mean plasma osmolality values were similar in the two groups. During hypertonic saline infusion, the 10 hypopituitary patients had varying degrees of subnormal arginine vasopressin responses to the increase in plasma osmolality. Urine-concentrating ability after dehydration also was lower in the patients, although overt polyuria was absent at the time of this study. These results indicate that the osmoregulation of arginine vasopressin secretion is frequently impaired in postpartum hypopituitarism, suggesting neurohypophyseal damage.
Asunto(s)
Arginina Vasopresina/fisiología , Hipopituitarismo/fisiopatología , Neurohipófisis/fisiopatología , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Concentración Osmolar , Hormonas Adenohipofisarias/sangre , Embarazo , Prolactina/sangre , Cloruro de Sodio/farmacología , Equilibrio HidroelectrolíticoRESUMEN
Fifty Japanese patients with insulin-dependent diabetes mellitus (IDDM) and 94 normal subjects were genotyped for BglII restriction-fragment-length polymorphism (RFLP) of the T-lymphocyte-receptor beta-chain (TLR beta)-region gene and analyzed in relation to HLA-DR phenotypes. The antigen frequencies of DR4 and DR9 in the IDDM population were significantly higher than those in the normal population, with relative risks of 1.87 (P less than .02) and 2.42 (P less than .01), respectively. Hybridization of digested DNA with the TLR beta probe revealed two alleles of 9.3 and 8.6 kilobases (kb). The allele frequency of 8.6 kb in patients with IDDM (79%) was significantly (P less than .05) higher than that in normal subjects (64%). When TLR beta-region RFLP in IDDM was further analyzed with respect to the HLA-DR phenotypes, the frequency of 8.6 kb was significantly increased in patients with DR4 but not DR9 (DR4/X) and those with DR9 but not DR4 (DR9/X) compared with the frequency found in normal subjects (P less than .05); the relative risks of 8.6 kb in DR4/X and DR9/X were 2.77 and 4.98, respectively. Although the frequencies of HLA-DR phenotypes and of TLR beta-region RFLP in IDDM and normal subjects were apparently different from those reported for Caucasians, this population-association study indicates that in the Japanese, genes conferring susceptibility to IDDM exist near or at the HLA-DR and the TLR beta loci, as has been demonstrated in Caucasians.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DR/genética , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Antígenos de Linfocitos T/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-betaAsunto(s)
Glucagón/sangre , Neurotensina/análogos & derivados , Neurotensina/farmacología , Animales , Glucemia/metabolismo , Glucagón/metabolismo , Insulina/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Neurotensina/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
Isolated rat pancreatic islets were preincubated in a medium with 16.7 mM glucose and incubated with 5.5 mM glucose. Both histamine (100 microM) and neurotensin (100 nM) stimulated glucagon release from the isolated islets, but not insulin release. The stimulation of glucagon release occurred in the presence of 10 and 100 nM neurotensin, while the release of insulin was inhibited in the presence of 1 and 10 nM neurotensin. The neurotensin-induced glucagon release was completely inhibited by 1 mM metiamide, an histamine H2-receptor antagonist, added to the incubation medium and not inhibited by 1 mM diphenhydramine, an histamine H1-receptor antagonist. The results indicate that the histaminergic mechanism, including the H2-receptor system, may be involved in neurotensin-induced glucagon release from the endocrine pancreas.
Asunto(s)
Glucagón/metabolismo , Histamina/farmacología , Islotes Pancreáticos/metabolismo , Neurotensina/farmacología , Animales , Arginina/farmacología , Difenhidramina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Metiamida/farmacología , Ratas , Ratas EndogámicasRESUMEN
Major hepatectomy in the dog induced a 50% decrease in peripheral serum glucose, a 11-fold increase in portal plasma glucagon and a 36-fold increase in the portal glucagon/insulin ratio 3 hr after operation. Peripheral serum glucose levels were inversely correlated to the logarithmic value of portal plasma glucagon (r = -0.50, p less than 0.01) and that of the portal glucagon/insulin ratio (r = -0.85, p less than 0.01) for 1-6 hr after operation. The ratio of peripheral to portal plasma glucagon was also inversely correlated to the logarithmic value of portal plasma glucagon (r = -0.59, p less than 0.01). In case of glucose infusion, plasma glucagon levels were not elevated after major hepatectomy. The data suggest that glucose deficiency after major hepatectomy in the dog may cause hyperglucagonemia with an enhanced glucagon requirement.
Asunto(s)
Glucagón/metabolismo , Hepatectomía , Insulina/metabolismo , Animales , Glucemia/análisis , Perros , FemeninoRESUMEN
Administration of neurotensin to dogs resulted in rises in circulating blood glucose, glucagon and insulin levels, the rise in glucagon being more pronounced than that in insulin. Infusion of somatostatin along with neurotensin suppressed glucagon and insulin responses to neurotensin and prevented the rise in blood glucose levels. These results suggest that the hyperglycemia seen after neurotensin is due to neurotensin stimulation of glucagon release over insulin release.